Infection by several Ebola virus species is associated with severe viral hemorrhagic fever (VHF) in humans. To date, significant Ebola virus outbreaks in central and western Africa have been associated with the Ebola- Zaire (EBOV), Sudan (SUDV) and Bundibugyo (BDBV) species with case-fatality rates ranging from 40-90%. During the 2014-2016 EBOV outbreak ~ 11,325 people died from Ebola VHF. Given the lack of approved treatments and prophylactics, the high mortality rate associated with infection, and the potential for geographical transplantation the development of broad spectrum Ebola virus antivirals for the treatment and prophylaxis of VHF remains an NIAID high priority. In this proposal we detail plans to optimize an attractive hit-to-lead chemical series of Ebola virus cell entry inhibitors utilizing VSV pseudotype viruses expressing Ebola virus glycoproteins along with confirmatory BLS4 native virus assays and initial vitro and in vivo ADMET studies to provide a lead compound compatible with oral administration for proof on concept studies in an in vivo animal efficacy model.